Liminal Biosciences's PBI-4050 Reduces Pulmonary Hypertension, Preclinical Data Show - Pulmonary Hypertension News
Liminal Biosciences's PBI-4050 Reduces Pulmonary Hypertension, Preclinical Data Show - Pulmonary Hypertension News |
| Posted: 27 Nov 2019 08:00 AM PST New preclinical data supports the positive effects of Liminal Biosciences's lead candidate, PBI-4050, in reducing pulmonary hypertension and the abnormal enlargement of the heart's right ventricle muscle. The company presented its latest data on two posters at the American Heart Association 2019 conference, held recently in Philadelphia. The posters are titled "PBI-4050 Reduces Angio-proliferative Pulmonary Arterial Hypertension: Decreased Human Pulmonary Artery Smooth Muscle Cell Proliferation and Microvascular Endothelial Cell Endoplasmic Reticulum Stress," and "Transcriptomics of Lung Molecular Remodeling in Pulmonary Hypertension Due to Left Heart Disease: Benefits of Combined PBI-4050/Valsartan Therapy." PBI-4050 is an oral therapy originally developed to treat idiopathic pulmonary fibrosis (IPF). The therapy helps regulate both inflammation and scarring, or fibrosis, by reducing the level of pro-fibrotic cytokines — chemical signals that promote scarring. Apart from IPF, previous data showed that PBI-4050 reduced pulmonary hypertension (PH) and right ventricular hypertrophy, which is the abnormal enlargement of the heart right ventricle muscle, common among PH patients. In the first study, researchers used a rat model that closely mimics severe pulmonary arterial hypertension (PAH) in humans, called Sugen/chronic hypoxia. The team assessed the effects of PBI-4050 compared with that of sildenafil or a placebo. Sildenafil, marketed by Pfizer as Revatio, is an approved oral medication for PAH that widens the blood vessels of the lungs, lowering blood pressure. The rats were treated with PBI-4050 (200 mg/kg/day), sildenafil (100 mg/kg/day), or placebo for 4 weeks. The results showed that PBI-4050 effectively reduced PAH, right ventricular hypertrophy and dysfunction. It also decreased the scarring of blood vessels. Sildenafil showed comparable effects, but was better at improving certain parameters of right ventricular (RV) function. These parameters include right ventricular systolic pressure, tricuspid annular plane systolic excursion (TAPSE) — a measure of the efficiency of the right ventricle to eject blood — and RV contractility. Contractility is the inherent strength and vigor of the heart's contraction. Genetic analyses of the rats' lungs showed that PBI-4050 decreased the levels of the genes that promote fibrosis, including α-smooth muscle actin (α-SMA). It also decreased the levels of the genes that promote inflammation, which include IL-6 and MCP-1. The analyses also showed that PBI-4050 markedly reduced a specific stress pathway, called ER stress, in endothelial cells, which are the cells lining the blood vessels. Overall, the results showed that PBI-4050 reduced the expression of profibrotic and proinflammatory markers. This supports the therapy's development as a treatment for PAH, the researchers said. In the second poster, the investigators used an animal model to study how PBI-4050 could modulate fibrosis in the lung after a heart attack (myocardial infarction) causing PH. Two days after the heart attack, the team administered PBI-4050, valsartan — an angiotensin receptor blocker that lowers blood pressure — or a combination of the two. This treatment was continued for five weeks. The researchers then analyzed gene activity in the lung tissue after treatment. The results suggested that the combination of PBI-4050 and valsartan improved right ventricular hypertrophy and function. The gene activity seen after treatment mirrored these biological effects. "We showed that, after large MI [myocardial infarction] causing PH, PBI-4050 therapy provides added benefit to valsartan, by … improving RV function and hypertrophy," the researchers said. "Although not a current focus of the Company's research program, this new preclinical data adds to our body of knowledge of our lead compound, PBI-4050," Kenneth Galbraith, CEO of Liminal BioSciences, said in a press release:  Patricia holds her Ph.D. in Cell Biology from University Nova de Lisboa, and has served as an author on several research projects and fellowships, as well as major grant applications for European Agencies. She also served as a PhD student research assistant in the Laboratory of Doctor David A. Fidock, Department of Microbiology & Immunology, Columbia University, New York. × Patricia holds her Ph.D. in Cell Biology from University Nova de Lisboa, and has served as an author on several research projects and fellowships, as well as major grant applications for European Agencies. She also served as a PhD student research assistant in the Laboratory of Doctor David A. Fidock, Department of Microbiology & Immunology, Columbia University, New York. Latest Posts  |
| Pulmonary arterial hypertension targeted for new treatment by Sheffield scientists - EurekAlert Posted: 15 Nov 2019 12:00 AM PST 
Scientists at the University of Sheffield, working in collaboration with drug and vaccine developer Kymab Ltd, Cambridge, have identified a novel antibody that has the potential to become a new treatment for pulmonary arterial hypertension (PAH). Research published today in Nature Communications (Friday 15 November 2019) from the University's Department of Infection, Immunity and Cardiovascular Disease shows that treatment with a specific antibody can reverse the process behind the development of PAH, and will now be considered for clinical development. Pulmonary arterial hypertension or PAH is a rare but fatal disease with the only cure being lung transplantation. It results in high blood within the lungs due to the constriction and overgrowth of the cells within the arteries that supply blood to the lungs. Over time this growth restricts blood flow through these vessels, putting strain on the heart and eventually causing heart failure. The study found osteoprotegerin (OPG) - which has primarily been thought to just regulate bone density - drives the process behind the growth of the cells within the blood vessel walls affected in PAH. A therapeutic human anti-OPG antibody was found to stop the progress of the disease in experimental lab rodent and cell models, and reverse the proliferation of cells which cause the arteries to thicken. Allan Lawrie, Professor of Translational Cardiopulmonary Science at the University of Sheffield, said: "Current treatments for PAH ease the symptoms by relaxing and dilating the affected blood vessels which can help extend the life expectancy for those living with PAH, but they do not stop the underlying drivers of the disease. "The great benefit of this research is the potential for this new drug to be used in conjunction with current treatments, to ease symptoms and further halt or reverse the progression of the disease." PAH is a rare disease, affecting less than 1 in 2000 people and has 'orphan disease' designation, meaning that despite smaller numbers of patients affected there is a recognised need for effective treatments to be developed. Sheffield Teaching Hospitals NHS Foundation Trust and the University of Sheffield are one of the largest specialist centres in the world for diagnosis, treatment and leading research into PAH, with this study being the first time that this particular mechanism of the disease has been targeted with a therapeutic human antibody. "The support from the Medical Research Council in collaboration with Kymab Ltd - which generated the antibody - and the British Heart Foundation to fund this research through the recently formed Donald Heath Research Programme in Sheffield is a hugely significant recognition of the importance of research in this field of medicine which aims to improve the outcome for patients suffering from PAH," added Professor Lawrie. ### The University of Sheffield With almost 29,000 of the brightest students from over 140 countries, learning alongside over 1,200 of the best academics from across the globe, the University of Sheffield is one of the world's leading universities. A member of the UK's prestigious Russell Group of leading research-led institutions, Sheffield offers world-class teaching and research excellence across a wide range of disciplines. Unified by the power of discovery and understanding, staff and students at the university are committed to finding new ways to transform the world we live in. Sheffield is the only university to feature in The Sunday Times 100 Best Not-For-Profit Organisations to Work For 2018 and for the last eight years has been ranked in the top five UK universities for Student Satisfaction by Times Higher Education. Sheffield has six Nobel Prize winners among former staff and students and its alumni go on to hold positions of great responsibility and influence all over the world, making significant contributions in their chosen fields. Global research partners and clients include Boeing, Rolls-Royce, Unilever, AstraZeneca, GlaxoSmithKline, Siemens and Airbus, as well as many UK and overseas government agencies and charitable foundations. Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.  |
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